The increasing availability of novel genetic mutations linked to ALS and Parkinson's disease (PD) provides us more molecular targets to investigate the underlying pathological mechanisms of these two common neurodegenerative movement disorders. Besides our continuous efforts on ALS research, mainly on newly developed VAPB transgenic mice, our current research more focuses on PD, in particular, on the two dominant mutations in alpha-synuclein and LRRK2. We have generated a series of conditional alpha-synuclein and LRRK2 transgenic mice that allow us to systematically evaluate the significance of where and when the expression of these disease-causing mutations affects the onset and progression of neuron degeneration. We are very excited about the newly developed PITX3-IRES-tTA knock-in mice that can specifically drive the expression of transgene in midbrain dopaminergic neurons. Besides studying PD-related monogenic mutation in mice, we are also interested in studying the genetic interactions between&#61472;alpha-synuclein, LRRK2 and other PD-related genes by crossbreeding different PD mouse models. We have shown that co-expression of mutant alpha-synuclein and LRRK2 causes synergistic toxicity to striatal neurons in transgenic mice with the forebrain expression of these two PD-related mutations. We will next to investigate whether co-expression of mutations in alpha-synuclein and LRRK2 causes a similar synergistic toxicity to nigrostriatal dopaminergic neurons in PITX3-IRES-tTA/A53T/G2019S transgenic mice. More importantly, we will employ multidisciplinary approaches to identify molecular pathways critical for the function and survival of striatal medium spiny neurons and nigrostriatal dopaminergic neurons. With the continuous strong support from the intramural research program of NIA, we are confident in keeping making solid progress in studying the pathobiological mechanisms of ALS and PD.